HPV transcript expression affects cervical cancer response to chemoradiation.

Jin Zhang,Michael Goldstein,Naoshad Muhammad,Christopher A Miller,Matthew Inkman,Ramachandran Rashmi,Stephanie Markovina,Perry W Grigsby,Michael D Mclellan,Julie K Schwarz,Nishanth Gabriel,Fiona J Ruiz

doi:10.1172/jci.insight.138734

Abstract

Persistent HPV infection is causative for the majority of cervical cancer cases; however, current guidelines do not require HPV testing for newly diagnosed cervical cancer. Using an institutional cohort of 88 patients with cervical cancer treated uniformly with standard-of-care chemoradiation treatment (CRT) with prospectively collected clinical outcome data, we observed that patients with cervical tumors containing HPV genotypes other than HPV 16 have worse survival outcomes after CRT compared with patients with HPV 16+ tumors, consistent with previously published studies. Using RNA sequencing analysis, we quantified viral transcription efficiency and found higher levels of E6 and the alternative transcript E6*I in cervical tumors with HPV genotypes other than HPV 16. These findings were validated using whole transcriptome data from The Cancer Genome Atlas (n = 304). For the first time to our knowledge, transcript expression level of HPV E6*I was identified as a predictive biomarker of CRT outcome in our complete institutional data set (n = 88) and within the HPV 16+ subset (n = 36). In vitro characterization of HPV E6*I and E6 overexpression revealed that both induce CRT resistance through distinct mechanisms dependent upon p53–p21. Our findings suggest that high expression of E6*I and E6 may represent novel biomarkers of CRT efficacy, and these patients may benefit from alternative treatment strategies.

Highlights

Cervical cancer is the fourth leading cause of cancer incidence and mortality in women worldwide [1]
Early-stage cervical cancers are managed by surgical resection, while locally advanced cases are treated with pelvic irradiation and the concurrent administration of cisplatin chemotherapy
We demonstrate that expression of an HPV genotype other than HPV 16 is a predictive biomarker for a poor disease response to the standard-of-care chemoradiation treatment (CRT) using a population of patients who were uniformly treated with standard-of-care CRT with prospectively collected clinical outcomes

Summary

Introduction

Cervical cancer is the fourth leading cause of cancer incidence and mortality in women worldwide [1]. Persistent HPV infection is causative for more than 91% of cervical cancer cases [3].Encoded within the HPV genome are 2 oncogenes that target key cell regulatory components. A few of the high-risk HPV genotypes are able to encode multiple E6 splice variants, all of the high-risk HPV genotypes encode the E6*I (hereinafter referred to as E6*) splice variant [9]. This primary alternatively spliced variant uses the first 5′ alternative splice site in the E6 open reading frame to generate a truncated E6 splice variant, E6*, and the full-length E7 transcript [8]. If HPV infection persists, the uncontrolled replication of the infected cell leads to the accumulation of mutations that can further deregulate and reprogram the cell, leading to tumorigenesis

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